The candidate's goals are to develop into an outstanding clinical scientist with an independent laboratory based research program within the next 5 years. The candidate, and candidate's department, is committed to the specialized study necessary to achieve this goal. Under the proposed plan, the candidate will transition from a full-time academic clinical surgeon into a clinical scientist through an intensive research experience under the guidance of world-renowned basic scientists in gene therapy, cartilage and bone biology. This proposed career development will capitalize on the candidate's recently completed (Jan 2002) 1-yr fellowship experience (F33AR08639-01) at the Center for Molecular Orthopedics at Brigham and Women's Hospital. The fellowship provided exposure to basic research skills in molecular biology of gene transfer, but further mentoring and greater time devotion will be necessary to generate an independent research effort. The goal of the proposed research project is to enhance the long-term healing of articular cartilage and subchondral bone injury. Injured or degenerate articular cartilage and underlying bone either does not heal or heals with a poor replacement tissue of inferior biomechanical function. We propose to deliver cartilage/bone morphogen genes and a chondroprotective gene efficiently to joints with cartilage injury using an appealing vector system for human gene delivery (AAV). We will investigate viral tropism to articular cells and develop novel AAV based vector systems for successful targeted delivery of our therapeutic genes to resident articular cells; chondrocytes, bone marrow-derived cells and synovial cells. Our objective is to use a gene delivery mechanism to compare the effectiveness of two growth factors, bone morphogenetic protein (BMP)- 2 and BMP-6, to promote the rate and integrity of cartilage repair, with and without the combination of an antagonist of cartilage degradation (Interleukin-1 receptor antagonist; Il-1 ra). The genes hBMP-2 and hBMP-6 offer therapeutic promise as supportive to chondrocyte proliferation and the endochondral ossification process necessary to heal articular cartilage defects and support the reformation of a secure cartilage-subchondral bone interface. IL-lra has already been demonstrated to ameliorate the articular cartilage degradation process to a degree that is clinically relevant in osteoarthritis models, including articular cartilage injury models. These genes, separately and in concert may significantly improve our current therapy options to the management of joint injury.